MeCP2 deficiency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affects UBE3A expression

Kirill Makedonski, Liron Abuhatzira, Yotam Kaufman, Aharon Razin, Ruth Shemer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

112 Scopus citations


Rett syndrome (RS) is a severe and progressive neurodevelopmental disorder caused by heterozygous mutations in the X-linked methyl CpG binding protein 2 (MeCP2) gene. MeCP2 is a nuclear protein that binds specifically to methylated DNA and functions as a general transcription repressor in the context of chromatin remodeling complexes. RS shares clinical features with those of Angelman syndrome (AS), an imprinting neurodevelopmental disorder. In AS patients, the maternally expressed copy of UBE3A that codes for the ubiquitin protein ligase 3A (E6-AP) is repressed. The similar phenotype of these two syndromes led us to hypothesize that part of the RS phenotype is due to MeCP2-associated silencing of UBE3A. Indeed, UBE3A mRNA and protein are shown here to be significantly reduced in human and mouse MECP2 deficient brains. This reduced UBE3A level was associated with biallelic production of the UBE3A antisense RNA. In addition, MeCP2 deficiency resulted in elevated histone H3 acetylation and H3(K4) methylation and reduced H3(K9) methylation at the PWS/AS imprinting center, with no effect on DNA methylation or SNRPN expression. We conclude, therefore, that MeCP2 deficiency causes epigenetic aberrations at the PWS imprinting center. These changes in histone modifications result in loss of imprinting of the UBE3A antisense gene in the brain, increase in UBE3A antisense RNA level and, consequently reduction in UBE3A production.

Original languageAmerican English
Pages (from-to)1049-1058
Number of pages10
JournalHuman Molecular Genetics
Issue number8
StatePublished - 15 Apr 2005

Bibliographical note

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This possibility is supported by the following facts. (i) The PWS-IC is methylated on the repressed maternal allele, whereas the active paternal allele is unmethylated (21,22). (ii) MECP2 binds to methylated DNA through its methyl binding domain (MBD) and recruits histone deacetylases (HDAC1 and 2) and histone H3(K9) methylase by its transcriptional-repression domain (TRD) (23,24).


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